High salt (HS) diet impairs the ability of resistance vessels to respond to vasodilator stimuli, without an increase in blood pressure, and angiotensin II (ANG II) suppression in response to HS diet appears to be a crucial factor contributing to impaired vascular relaxation. Recent studies suggest that increased oxidative stress in the microcirculation leads to impaired relaxation of arterioles and resistance arteries during HS diet. An unexplored question is whether local blood flow control is impaired by HS diet, potentially compromising the ability of salt-sensitive individuals to respond to circulatory stresses such as exercise, hemorrhage, or myocardial infarction. This study will investigate vascular alterations occurring in normotensive animals on a HS diet [with and without chronic i.v. infusion of a low (subpressor) dose of ANG II to prevent ANG II suppression]. Recovery of vascular relaxation mechanisms will also be evaluated following restoration oflow salt (LS) diet after an initial exposure to HS diet. Vascular control mechanisms will be evaluated by measuring the diameters of isolated resistance arteries and in situ arterioles, and by assessing cerebral bloodflow via laser Doppler flowmetry during exposure to different vasodilator stimuli. Changes in the levels of NO, superoxide, and key arachidonic acid (AA) metabolites will be evaluated in the various groups, and changes in gene expression with HS diet, restoration of LS diet, and low dose ANG II infusion will be investigated using immunoblotting and a temporal microarray approach. The central hypothesis of this study is that HS diet leads to a profound, but reversible, impairment of vascular relaxation mechanisms in resistance arteries as a result of increased oxidative stress. The specific aims of this project are to: 1) evaluate the role of oxidative stress and NOS uncoupling in contributing to impaired vascular relaxation in animals on HS diet; 2) identify specific vasodilator mechanisms that are restored by return to a LS diet or maintained by low dose ANG II infusion, and to define the temporal relationship between changes in plasma ANG II levels and altered vascular relaxation mechanisms; 3) determine the effects of HS diet, restoration of LS diet after exposure to HS diet, and low dose ANG II infusion on gene expression in resistance arteries,using a temporal microarray approach; and 4) evaluate the functional consequences of HS diet on blood flow regulation at the whole vascular bed level. These studies should provide important new information regarding the mechanisms by which HS diet leads to impaired relaxation of resistance arteries, the novel role of ANG II in maintaining vascular relaxation mechanisms in resistance vessels, and the functional impact of HS diet on blood flow regulation in the in vivo microcirculation.